1. Field of the Invention
The present invention relates to a novel process for preparing porphyrin derivatives, such as protoporphyrin (IX), and also to intermediates for the synthesis of these compounds.
2. Summary of the Related Art
Certain porphyrins are known and used for their biological or medical properties. By way of example, mention may be made of the following porphyrins of formula:
                in which:        Ra═—CH═CH2, then named protoporphyrin IX,        Ra═—CH2CH3, then named mesoporphyrin,        Ra═—CH(OH)CH3, then named hematoporphyrin,        Ra═H, then named deuteroporphyrin,        Ra═—CH2CH2COORb with Rb being a hydrogen atom or a methyl, ethyl, n-propyl or i-propyl group, then named coproporphyrin III,        Ra═—C(O)CH3, then named diacetyldeuteroporphyrin.        
These porphyrins can be used in the form of salts, for example of a salt with an alkali metal at the two acid functions, such as a sodium salt.
It is also possible, depending on the applications, for these porphyrins to be used in a complexed form, for example complexed with a metal such as Fe, or alternatively a metal salt such as FeCl or FeOH. The complex of protoporphyrin IX with Fe is called heme, that with FeOH is called hematin and that with FeCl is called hemin.
These porphyrins are most commonly prepared by hemisynthesis, which poses the problem of impurities of animal origin, in particular, that may be present. For certain applications, for example in the case of protoporphyrin (IX), or of its sodium salt, which may be used in cell culture media, the desire is to provide a completely synthetic preparation process which uses only products of synthetic origin. Certain processes of preparation by chemical synthesis of these compounds have already been proposed. The publications in J C S Perkin I, 1974, 1771-1781 and 1188-1194, for example, describe the preparation of protoporphyrin IX. A known method for preparing protoporphyrin, to which reference is made in these publications, is referred to as the MacDonald process and consists in coupling, in the presence of a metal cation M+ such as Zn2+ or Fe3+, the following two pyrromethanes (A) and (B):
                so as to give a porphodimethane structure (C):        
                which must subsequently be oxidized so as to form the metalated porphyrin (D):        

Such a method is in particular described in Science of Synthesis Houben-Weyl, vol. 17, 1081-1235 and in The porphyrin Handbook, vol. 1, synthesis and Chemistry, Academic Press, Boston, 2000.
It is subsequently necessary to demetalize the porphyrin, in the presence of sulfuric acid, if said porphyrin must be used in free form. The latter step in particular is not quantitative and the porphyrin obtained does not have a satisfactory degree of purity. The high —C(O)CH3 function must also be converted to —CH═CH2.